Evaluation of a multicomponent intervention consisting of education and feedback to reduce benzodiazepine prescriptions by general practitioners: The BENZORED hybrid type 1 cluster randomized controlled trial.

BACKGROUND: Current benzodiazepine (BZD) prescription guidelines recommend short-term use to minimize the risk of dependence, cognitive impairment, and falls and fractures. However, many clinicians overprescribe BZDs and chronic use by patients is common. There is limited evidence on the effectiveness of interventions delivered by general practitioners (GPs) on reducing prescriptions and long-term use of BZDs. We aimed to evaluate the effectiveness of a multicomponent intervention for GPs that seeks to reduce BZD prescriptions and the prevalence of long-term users. METHODS AND FINDINGS: We conducted a multicenter two-arm, cluster randomized controlled trial in 3 health districts in Spain (primary health centers [PHCs] in Balearic Islands, Catalonia, and Valencian Community) from September 2016 to May 2018. The 81 PHCs were randomly allocated to the intervention group (n = 41; 372 GPs) or the control group (n = 40; 377 GPs). GPs were not blinded to the allocation; however, pharmacists, researchers, and trial statisticians were blinded to the allocation arm. The intervention consisted of a workshop about the appropriate prescribing of BZDs and tapering-off long-term BZD use using a tailored stepped dose reduction with monthly BZD prescription feedback and access to a support web page. The primary outcome, based on 700 GPs (351 in the control group and 349 in the intervention group), compared changes in BZD prescriptions in defined daily doses (DDDs) per 1,000 inhabitants per day after 12 months. The 2 secondary outcomes were the proportion of long-term users (≥6 months) and the proportion of long-term users over age 65 years. Intention-to-treat (ITT) analysis was used to assess all clinical outcomes. Forty-nine GPs (21 intervention group and 28 control group) were lost to follow-up. However, all GPs were included in the ITT analysis. After 12 months, there were a statistically significant decline in total BZD prescription in the intervention group compared to the control group (mean difference: -3.24 DDDs per 1,000 inhabitants per day, 95% confidence interval (CI): -4.96, -1.53, p < 0.001). The intervention group also had a smaller number of long-term users. The adjusted absolute difference overall was -0.36 (95% CI: -0.55, -0.16, p > 0.001), and the adjusted absolute difference in long-term users over age 65 years was -0.87 (95% CI: -1.44, -0.30, p = 0.003). A key limitation of this clustered design clinical trial is the imbalance of some baseline characteristics. The control groups have a higher rate of baseline BZD prescription, and more GPs in the intervention group were women, GPs with a doctorate degree, and trainers of GP residents. CONCLUSIONS: A multicomponent intervention that targeted GPs and included educational meeting, feedback about BZD prescriptions, and a support web page led to a statistically significant reduction of BZD prescriptions and fewer long-term users. Although the effect size was small, the high prevalence of BZD use in the general population suggests that large-scale implementation of this intervention could have positive effects on the health of many patients. TRIAL REGISTRATION: ISRCTN ISRCTN28272199.

Evaluating the Implementation of a Multicomponent Intervention Consisting of Education and Feedback on Reducing Benzodiazepine Prescriptions by General Practitioners: BENZORED Hybrid Type I Cluster Randomized Controlled Trial.

BACKGROUND: General practitioners (GPs) in developed countries widely prescribe benzodiazepines (BZDs) for their anxiolytic, hypnotic, and muscle-relaxant effects. Treatment duration, however, is rarely limited, and this results in a significant number of chronic users. Long-term BZD use is associated with cognitive impairment, falls with hip fractures, traffic accidents, and increased mortality. The BENZORED IV trial was a hybrid type-1 trial conducted to evaluate the effectiveness and implementation of an intervention to reduce BZD prescription in primary care. The purpose of this qualitative study was to analyze the facilitators and barriers regarding the implementation of the intervention in primary care settings. METHODS: A qualitative interview study with 40 GPs from three Spanish health districts. Focus group meetings with GPs from the intervention arm of the BENZORED IV trial were held at primary healthcare centers in the three districts. For sampling purposes, the GPs were classified as high or low implementers according to the success of the intervention measured at 12 months. The Consolidated Framework for Implementation Research (CFIR) was used to conduct the meetings and to code, rate, and analyze the data. RESULTS: Three of the 41 CFIR constructs strongly distinguished between high and low implementers: the complexity of the intervention, the individual Stage of Change, and the key stakeholder's engagement. Seven constructs weakly discriminated between the two groups: adaptability in the intervention, external policy and incentives, implementation climate, relative priority, self-efficacy, compatibility, and engaging a formally appointed implementation leader. Fourteen constructs did not discriminate between the two groups, six had insufficient data for evaluation, and eleven had no data for evaluation. CONCLUSIONS: We identified constructs that could explain differences in the efficacy in implementation of the intervention. This information is relevant for the design of successful strategies for implementation of the intervention.

Cost-Effectiveness Analysis of Exenatide versus GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus.

OBJECTIVE: The aim of this study was to assess the efficiency of exenatide 2 mg/week compared with other glucagon-like peptide-1 (GLP-1) receptor agonists (dulaglutide 1.5 mg/week, liraglutide 1.2 mg/day, liraglutide 1.8 mg/day and lixisenatide 20 µg/day) in adult patients with type 2 diabetes mellitus (T2DM) not adequately controlled on metformin alone from the perspective of the Spanish National Health System (NHS). METHODS: Quality-adjusted life-years (QALYs) gained and total costs of each assessed drug combined with metformin (2 g/day) were estimated over a 40-year time horizon using the Cardiff Diabetes Model (based on UK Prospective Diabetes Study [UKPDS] 68 equations), which simulates disease progression considering the T2DM-related micro- and macrovascular complications, hypoglycaemia, nausea, body mass index (BMI) changes and treatment discontinuation due to adverse effects (AEs). Drug efficacy derived from an indirect comparison performed in a network meta-analysis. Patient characteristics were obtained from the literature. The baseline utility value (0.80) was derived from the PANORAMA study, applying utility decrements to micro- and macrovascular complications, hypoglycaemia episodes and changes in BMI. Treatment discontinuation due to AEs or poorly controlled diabetes (HbA1c > 7.5%) involved switching to second-line (basal insulin) or third-line (basal-bolus insulin) treatment. Total cost (€, 2018) included the costs of drug acquisition, hypoglycaemia, weight gain, micro- and macrovascular complications, nausea and treatment discontinuation due to AEs. An annual discount rate of 3% was applied to costs and outcomes. Deterministic and probabilistic sensitivity analyses (SA) were performed. RESULTS: In base-case, exenatide 2 mg/week resulted in more QALYs (8.26) than dulaglutide 1.5 mg/week (8.19 QALYs), liraglutide 1.2 mg/day (8.10 QALYs), liraglutide 1.8 mg/day (8.20 QALYs) and lixisenatide 20 µg/day (8.13 QALYs). Total cost/patient was €20,423.27 (exenatide 2 mg/week), €22,611.94 (dulaglutide 1.5 mg/week), €21,065.97 (liraglutide 1.2 mg/day), €24,865.69 (liraglutide 1.8 mg/day) and €21,334.58 (lixisenatide 20 µg/day). Deterministic SA confirmed the robustness of the model. In the probabilistic SA, 95-99% of the 1000 Monte Carlo iterations performed were under a hypothetical willingness-to-pay threshold of €20,000/QALY gained. CONCLUSIONS: Exenatide 2 mg/week would be a dominant strategy (more effective and less costly) versus the other GLP-1 receptor agonists assessed for the treatment of T2DM patients who are not adequately controlled on metformin alone.

Intervention to reduce benzodiazepine prescriptions in primary care, study protocol of a hybrid type 1 cluster randomised controlled trial: the BENZORED study.

INTRODUCTION: Benzodiazepines (BZDs) are mainly used to treat anxiety and sleep disorders, and are often prescribed for long durations, even though prescription guidelines recommend short-term use due to the risk of dependence, cognitive impairment, and falls and fractures. Education of general practitioners (GPs) regarding the prescription of BZDs may reduce the overuse and of these drugs.The aims of this study are to analyse the effectiveness of an intervention targeted to GPs to reduce BZD prescription and evaluate the implementation process. METHODS AND ANALYSIS: The healthcare centres in three regions of Spain (Balearic Islands, Catalonia and Community of Valencia) will be randomly allocated to receive a multifactorial intervention or usual care (control). GPs in the intervention group will receive a 2-hour workshop about best-practice regarding BZD prescription and BZD deprescribing, monthly feedback about their BZD prescribing practices and access to a support web page. Outcome measures for each GP are the defined daily dosage per 1000 inhabitants per day and the proportion of long-term BZD users at 12 months. Data will be collected from the electronic prescription database of the public health system, and will be subjected to intention-to-treat analysis. Implementation will be evaluated by mixed methods following the five domains of the Consolidated Framework For Implementation Research. ETHICS AND DISSEMINATION: This study was approved by the Balearic Islands Ethical Committee of Clinical Research (IB3065/15), l'IDIAP Jordi Gol Ethical Committee of Clinical Research (PI 15/0148) and Valencia Primary Care Ethical Committee of Clinical Research (P16/024). The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN28272199.

Intervención farmacéutica para reducir el riesgo de iatrogenia asociada a la combinación triple whammy / Pharmaceutical intervention to reduce the iatrogenic risk associated with the triple whammy combination

OBJETIVO: Analizar el efecto de una intervención para reducir el riesgo de iatrogenia asociada a prescripciones crónicas concomitantes de inhibidores de la enzima de conversión de angiotensina (iECA) y/o antagonistas del receptor de la angiotensina II (ARA-II) con diuréticos y antiinflamatorios no esteroideos (AINE), combinación denominada triple whammy (TW). DISEÑO: Estudio de intervención antes-después. Emplazamiento: Quince centros de salud de un sector sanitario (población de referencia de 292.746 pacientes). PARTICIPANTES: Un total de 260 pacientes con edad ≥18 años y prescripciones crónicas concomitantes de fármacos de los grupos terapéuticos (código ATC): diuréticos (C03), iECA/ARA-II (C09) y AINE (M01), en enero de 2015. INTERVENCIONES: Intervención doble durante febrero y marzo de 2015: educacional (sesión informativa) e individualizada (revisión de historias clínicas y recomendaciones al médico de cabecera). Mediciones principales: Se analizó el número de pacientes en los que se aceptó al menos una recomendación y el número de pacientes que continuaban con la combinación TW prescrita en junio de 2015. Se analizaron los datos mediante estadística descriptiva y se comparó la prevalencia de TW en junio de 2015 con la inicial mediante método híbrido de Newcombe-Wilson. RESULTADOS: Se incluyeron 260 pacientes. En 165 (63,5%) se realizó alguna recomendación, y en 97 (58,8%) se aceptó al menos una. En junio de 2015, 184 pacientes continuaban con la combinación TW. La prevalencia de TW tras la intervención disminuyó en 0,19/1.000 pacientes (IC 95%: 0,04/1.000 a 0,34/1.000; p = 0,017). CONCLUSIONES: La intervención realizada mejoró la prescripción y redujo el número de pacientes con la combinación TW

OBJECTIVE: To analyze the effect of an intervention to reduce the iatrogenic risk associated with concomitant treatment with angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin-II receptor blockers (ARB) with diuretics and nonsteroidal anti-inflamatory drugs (NSAID), combination known as triple whammy (TW). DESIGN: Uncontrolled before-after intervention study. LOCATION: 15 health centers from a health area (reference population of 292.746 habitants). PARTICIPANTS: 260 patients ≥18 years old with chronic and concomitant prescriptions of drugs from the therapeutic groups (ATC code): diuretics (C03), ACEi/ARBs (C09) and NSAID (M01) during the month of January 2015. INTERVENTIONS: A double intervention was conducted during February and March 2015: an educational part, which consisted of an informative session, and an individualized part, in which recommendations to general practitioner were assessed after reviewing medical records. MAIN MEASUREMENTS: The number of patients in whom at least one intervention was accepted and the number of patients who continued on TW combination in June 2015, were analyzed. Results were analyzed using descriptive statistics and the prevalence of TW was compared with the one in June 2015 using the Newcombe-Wilson's hybrid method. RESULTS: 260 patients were included in the study. Recommendations were made in 165 patients (63.5%) and at least one was accepted in 97 (58.8%) patients. In June 2015, 184 patients continued with the TW combination. The TW prevalence decreased by 0.19/1,000 patients (IC 95%: 0.04/1,000 to 0.34/1,000; P=0.017) after the intervention. CONCLUSIONS: The intervention improved the prescription and reduced the number of patients on TW combination

[Pharmaceutical intervention to reduce the iatrogenic risk associated with the triple whammy combination]. / Intervención farmacéutica para reducir el riesgo de iatrogenia asociada a la combinación triple whammy.

OBJECTIVE: To analyze the effect of an intervention to reduce the iatrogenic risk associated with concomitant treatment with angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin-II receptor blockers (ARB) with diuretics and nonsteroidal anti-inflamatory drugs (NSAID), combination known as triple whammy (TW). DESIGN: Uncontrolled before-after intervention study. LOCATION: 15 health centers from a health area (reference population of 292.746 habitants). PARTICIPANTS: 260 patients ≥18 years old with chronic and concomitant prescriptions of drugs from the therapeutic groups (ATC code): diuretics (C03), ACEi/ARBs (C09) and NSAID (M01) during the month of January 2015 INTERVENTIONS: A double intervention was conducted during February and March 2015: an educational part, which consisted of an informative session, and an individualized part, in which recommendations to general practitioner were assessed after reviewing medical records. MAIN MEASUREMENTS: The number of patients in whom at least one intervention was accepted and the number of patients who continued on TW combination in June 2015, were analyzed. Results were analyzed using descriptive statistics and the prevalence of TW was compared with the one in June 2015 using the Newcombe-Wilson's hybrid method. RESULTS: 260 patients were included in the study. Recommendations were made in 165 patients (63.5%) and at least one was accepted in 97 (58.8%) patients. In June 2015, 184 patients continued with the TW combination. The TW prevalence decreased by 0.19/1,000 patients (IC 95%: 0.04/1,000 to 0.34/1,000; P=0.017) after the intervention. CONCLUSIONS: The intervention improved the prescription and reduced the number of patients on TW combination.